PIDs are often associated with autoimmunity due to dysregulation of the immune system as a whole. Clinical phenotypes are heterogeneous and often overlapping and, while in most patients a monogenic cause of disease has been identified, recent advancements made in genetic analysis, in particular with the introduction of high throughput techniques, reveal that a polygenic cause is likely. Our aim is to investigate the genetic background of patients with signs of immunedysregulation and autoimmunity, and to evaluate the pathogenicity of gene variants identified through extensive functional studies.
We selected nineteen patients, referring to the Haemato-Oncology Department of A. Meyer Children’s Hospital, with signs of immunedysregulation and autoimmunity and we performed extended immunophenotyping and Next Generation Sequencing (NGS) analysis of 50 PID-associated genes.
In six patients we identified a single gene as responsible of the clinical feature. In particular, we identified two patients with STAT3 GOF, one with an activating PIK3CD mutation, and three patients harboring mutations in CTLA4, RAG1 and FAS genes, respectively. Most of them also harbor variants in multiple genes and some of these are recurrently mutated in more then one patient: WAS, DOCK8, CASP10, CASP8, NFATC2 and FCGR3A. Further studies are ongoing to validate the effect of gene variants identified.
Our results suggest that the old hypothesis, based on a single gene mutation as cause of disease, should be revised in favor of the concept that "is the sum that causes the effect" and that a different point of view on PIDs seems inevitable.